DESCRIPTION: Pulmonary drug delivery is increasingly used for both treatment of lung diseases (such as asthma and chronic obstructive pulmonary disease) and in delivering drugs to the systemic circulation. To reach the desired effectiveness and safety of orally/nasally inhaled drugs, appropriate deposition of drugs on targeted region is essential. Due to complex pharmaceutical and physiological factors underlying bioavailability of inhaled drug products, computational modeling tools are urgently required to provide mechanistic insights of involved delivery processes and to estimate efficacy of pulmonary drug delivery in an accurate and efficient manner. Therefore, in this project, we propose to develop a novel multi-scale computational tool to simulate deposition, dissolution, absorption, transport, clearance, and actions of inhaled drug products within an integral framework of computational fluid dynamics (CFD) and PBPK-PD models. In Phase I, we will (1.) develop the hybrid CFD model of particle deposition in the entire human airways, (2.) extend the CFD models accounting for various physiological and pathological settings, and (3.) integrate CFD deposition models with pharmacokinetic models to estimate various pharmaceutical and physiological factors on pulmonary drug delivery. The associated computational investigations will greatly facilitate drug development by identifying key biopharmaceutical factors affecting efficacy and safety of inhaled drugs. In Phase II, we will further improve the computational tool model developed in Phase I by focusing on integration with physiology and compound databases, model calibration/validation, development of the software GUI, and demonstration of more pharmaceutical applications. The proposed computational tool will provide a mechanism-based virtual platform to investigate interactions between drug delivery systems and physiological/pathological systems, to provide mechanistic insights into key aspects affecting efficacy and safety of inhaled drug products, and to guide optimal designs of pulmonary drug delivery systems.